Prostate cancer is known to commonly metastasize to bone. One of the important mediators of prostate cancer cell proliferation is androgens functioning through the androgen receptor (AR). In addition to prostate cancer cell proliferation, androgens also function to regulate osteoblasts, osteoclasts, and bone resorption. It is therefore possible that the ability of prostate cancer cells to adhere to bone and alter bone turnover resulting in bone remodeling is related to the function of AR in prostate cancer cells and in the bone. AR activity in prostate cancer cells may result in the production of growth factors that stimulate bone remodeling. Similarly, AR action in osteoblasts and osteoclasts may contribute to prostate cancer proliferation or adherence at the metastatic site. To investigate the potential cooperative role of AR in prostate cancer and bone at metastatic sites, both in vitro and in vivo model systems will be used. We have previously generated mice using lox-Cre methodology that enable us to remove AR in the whole animal or in a cell-type specific manner, including the removal of AR in osteoclasts and osteoblasts. We have also generated a subline of the AR negative prostate cancer cell PC3 that expresses AR from the AR promoter. Four specific aims are proposed making use of these reagents: Specific Aim 1, to determine the role of AR in bone remodeling by prostate cancer cells in an in vitro model system; Specific Aim 2, to determine the role of AR in an in vivo model of prostate cancer metastasis; Specific Aim 3, to determine the role of osteoclast AR function in an in vitro and in vivo model of prostate cancer metastasis; and Specific Aim 4, to determine the role of osteoblast AR function in an in vitro and in vivo model of prostate cancer metastasis. The success of this proposal will allow a better understanding of the role of androgen in the metastatic spread of prostate cancer to bone and the molecular mechanism of bone remodeling by prostate cancer cells.